Pharmaceutical composition for compressed annular tablet with molded triturate tablet for both intraoral and oral administration

ABSTRACT

New pharmaceutical compositions in unit dosage form are disclosed for both intraoral and oral administration to a patient, said unit dosage form configured to be placed intraorally of said patient, which comprises:
         (a) as a first portion, at least one discrete molded triturate tablet comprising a therapeutically effective amount of at least one pharmaceutically active ingredient capable of intraoral administration; and   (b) as a second portion located around the said first portion, a therapeutically effective amount of at least one pharmaceutically active ingredient capable of oral administration and which is releasable and orally ingestible by the patient after the molded triturate tablet has disintegrated or has dissolved intraorally.

FIELD OF THE INVENTION

This invention relates to a pharmaceutical composition that providesboth for sublingual, buccal or vestibular mucosa or gingivalapplication, hereafter referred to as intraoral administration and forchewed or sucked or swallowed hereafter referred to as oraladministration. The pharmaceutical composition consists of two combinedtablet portions, (1) a triturate tablet molded within the annulae of asecond portion, and (2) a compressed tablet with a central cavity,hereafter referred to as a compressed annular tablet—CAT. The completedosage form, hereafter referred to as compressed annular tablet withtriturate tablet or CAT/T, comprises the triturate tablet molded intothe compressed annular tablet through a manufacturing process. Moreparticularly this invention relates to a triturate tablet compositioncontaining at least one pharmaceutically active ingredient capable ofintraoral administration and a compressed annular tablet with at leastone pharmaceutically active ingredient capable of oral administrationonce the intraorally administered active ingredient has beensubstantially released. The invention further relates to a method ofadministering a pharmaceutical composition for both intraoral and oraladministration to a patient. Furthermore, this invention combines twodistinctly different pharmaceutical manufacturing processes to form onesolid dosage unit: (1) employing dry powders or dried granulation toform a compressed annular tablet manufactured on a rotary tablet press,and (2) employing semi wet powders to form a molded triturate tabletmanufactured on a tablet triturate machine.

BACKGROUND OF THE INVENTION

Intraoral administration of medicaments has been carried out accordingto the prior art. See U.S. Pat. No. 4,229,447 to PORTER. This patentdiscloses the intraoral administration of benzodiazepines includingdiazepam, lorazepam, oxazapam, temazapam, and chlordiazepoxide.According to Porter it is known in the art to administer benzodiazapineseither orally or parenterally (i.e. by injection), especiallyintramuscularly or subcutaneously. Administering benzodiazepines byinjection enables rapid attainment of effective plasma concentrations,that is more rapid than the plasma concentrations obtained followingoral administration. One advantage of the intraoral administration asopposed to parenteral administration is that there is no injection sitewhere pain and inflammation may develop. Another such advantage is thatintraoral administration does not require sterilization of thepreparations and the hypodermic syringes. Furthermore, in manysituations self-administration of a medicament by parenteral means isnot possible for a patient.

In U.S. Pat. No. 5,739,136 to Ellinwood Jr. et al the medicamentselected for intraoral administration is one that if given by oraladministration is metabolized to an unwanted or aversive metabolite thatis increasingly formed during gastrointestinal tract absorption andsubsequent portal vein transport into the liver. Examples of suchmedicaments include not only the benzodiazepines especially atrifluorobenzodiazepine such as quazepam, but also other medicamentswhere it is advantageous to avoid first-pass metabolism such as theantianxiety/anticonvulsant/antihypnotic agents propoxyphene, nefazodone,trazodone, clormipramine, bupropion and combinations thereof. UnlikePorter, Ellinwood Jr. et al is not only concerned with rapidly attainingeffective plasma concentrations of the intraorally administeredmedicament, but is especially concerned that the medicament include adrug where first pass-metabolism is to be avoided. The intraoraladministration of the antianxiety/anticonvulsant/antihypnotic agentsdecreases the metabolism to the undesired metabolites.

In U.S. Pat. No. 6,183,778 to Jagotec AG, et al. the patent describes amultiple layer tablet capable of liberating one or more drugs atdifferent release rates. This multi-layer dosage form is intended solelyfor oral administration and therefore must undergo first passmetabolism. Although it contains multiple releasing layers there is nodosage mechanism to provide the advantages presented by intraoraladministration.

Remingtons, The Science and Practice of Pharmacy, 20th Ed., contains acomplete history of dosage forms, including compressed tablets andtriturate tablets; therefore, in the present invention no novelty isclaimed in the broad practice of producing compressed tablets from drypowder or granulation or triturate tablets molded from a semi-wetpowders. The uniqueness of the composition of this invention resides inits ability to provide in one dosage form the best features of both thecompressed tablet and the triturate tablet.

The unique features of compressed tablets are well known in the art andis the dosage form most commonly employed as the method of choice fororal administration through which the tablets are digested and the drugabsorbed into systemic circulation. Compressed tablets are not fragileand can withstand substantial handling without chipping or cracking. Thecompressed tablets can be formulated to provide disintegration and ordissolution of the active(s) at a specified time range after ingestion.They can be chewed but when used in this manner the tablets may losesome of their versatility. Compressed tablets can also be coated with amixture containing a drug which will dissolve before the bulk of thetablet and may be absorbed intraorally. Compressed tablets may belayered, with one or more layers formulated to give early and rapiddissolution of drug in those layers as well as sustained dissolution ofdrugs in those layers. Compressed tablets may contain beads that aremade of drugs in sustained-release or delayed-release forms in thetablet matrix.

Normally compressed tablets are uniformly solid but in this invention byemploying tooling with a core rod, a ring shaped or annular tablet isproduced, commonly referred to as a compressed annular tablet (CAT).Compressed tablets generally are intended to remain intact and notdisintegrate until they reach the stomach or intestine. Compressedtablets are generally formulated with appropriate diluents or bindersand/or polymers or waxes to obtain a desired appropriate hardness andare formulated as immediate, sustained or delayed released tablets.

Molded tablet triturates are, on the other hand, less versatile thancompressed tablets. Tablet triturates usually are made from moistmaterial comprising mainly one or more water soluble sugars. After themoist mass is incorporated in the mold to form a tablet triturate, thewet tablet triturates are ejected and dried. The resulting tablettriturates are generally more porous than the compressed tablets. Theirmain advantage is being rapidly disintegradable and soluble ordispersible in salivary fluid. They therefore lend themselves tointraoral administration and the avoidance of first pass metabolism.Triturate tablets have been more characterized by the disadvantages offriability or softness and thus require careful handling to preventchipping and breaking particularly on their edges. In the presentinvention this disadvantage is overcome by molding and hence protectingthe triturate tablet within center cavity of the compressed annulartablet, thereby eliminating the friability of the triturate whileretaining the advantage of a rapidly soluble triturate tablet.

Nowhere in the literature is there a preparation of a triturate tabletwhich is molded within a compressed annular tablet.

Nowhere in the prior art references is there a disclosure of apharmaceutical composition of a compressed annular tablet with a moldedtablet triturate that effectively administers a therapeuticallyeffective amount of pharmaceutically active ingredients by bothintraoral means to obtain a rapid onset of desired therapeutic effectvia plasma concentration and by oral means to obtain a more sustainingas well as complementary therapeutic effect.

OBJECTS OF THE INVENTION

It is an object of the invention to provide a pharmaceutical compositioncontaining at least one pharmaceutically active ingredient capable ofintraoral administration and at least one pharmaceutically activeingredient capable of oral administration and which is releasable andorally ingested by the patient after the pharmaceutically activeingredient capable of intraoral administration has disintegrated or hasdissolved intraorally. It is a further object of the invention toprovide a process for the preparation of a pharmaceutical compositioncontaining at least one pharmaceutically active ingredient capable ofintraoral administration and at least one pharmaceutically activeingredient capable of oral administration and which is orally ingestedby the patient after the pharmaceutically active ingredient capable ofintraoral administration has disintegrated or has dissolved intraorally.

It is a further object of the invention to provide a method of treatmentemploying a new pharmaceutical composition and dosage form whichcombines two portions, (1), a triturate tablet molded within the annularof the second portion (2), a compressed annular tablet (CAT). Thecomplete dosage form, hereafter referred to as CAT/T comprises thetriturate tablet molded into the compressed annular tablet through aunique Imanufacturing process.

It is a further object of this invention to provide a method oftreatment with this new dosage form which has pharmaceuticalcompositions for both intraoral and oral administration that is easilyadministrable to a patient so as to maximize therapeutic effectivenessand minimize side effects.

SUMMARY OF THE INVENTION

We have found that the object of this invention can be achieved by a newpharmaceutical dosage form that combines both a triturate tablet, and acompressed annular tablet. The active ingredient for intraoraladministration is contained in the first releasable portion, thetriturate tablet which has been molded into the cavity of the secondportion, a compressed annular tablet, which is designed to act as themold to form the triturate tablet and also contains the activeingredients for oral administration. According to one feature thepresent invention is directed to a method of treating a patient byintraorally administering to the patient a therapeutically effectiveamount of a pharmaceutically active ingredient capable of intraoraladministration. The second portion, contains a therapeutically effectiveamount of a pharmaceutically active ingredient capable of oraladministration which is orally ingested by the patient after the moldedtriturate tablet containing active ingredient capable of intraoraladministration has disintegrated or has substantially dissolvedintraorally. According to a preferred feature of the present invention,the pharmaceutical in unit dosage form is in the form, CAT/T, containstwo portions: a compressed annular tablet, CAT, and molded trituratetablet, T, which is molded within the CAT.

The dosage unit for both intraoral and oral administration is configuredto be placed intraorally and comprises:

-   -   (a) as a first releasable portion, one discrete triturate        tablet (T) unit comprising a therapeutically effective amount of        one or more pharmaceutically active ingredients capable of        intraoral administration; and    -   (b) as a second portion located around the first portion        consisting of a compressed annular tablet (CAT) containing a        therapeutically effective amount of at least one        pharmaceutically active ingredient capable of oral        administration and which is orally ingested by the patient after        the molded triturate tablet has disintegrated or substantially        dissolved intraorally.

The pharmaceutical dosage form of this invention may be administeredpreferably once or more times per day as well as administered in themorning (AM) or evening (PM). The dosage form contains, for intraoraldosing 1 mcg to 50 mg, preferably 5 mcg to 40 mg and more preferably 10mcg to 30 mg pharmaceutically active ingredient capable of intraoraladministration, and for oral dosing 0.5 mcg to 2 Gm, preferably 5 mg to1000 mg and more preferably 10 mg to 500 mg of the pharmaceuticallyactive ingredient capable of oral administration.

The present compositions are best suited where disease symptoms are suchthat both rapid relief of some of these symptoms are required as well asa continuation in controlling similar or other symptoms. Thus the moldedtriturate tablet unit containing pharmaceutical active ingredient(s)capable of intraoral administration provides rapid release forabsorption of medicament for rapid relief of symptoms while thecompressed annular tablet containing pharmaceutical active ingredient(s)capable of oral administration and releasing the medicament in animmediate or a sustained or delayed released manner to provide acontinuation in control in similar or other symptoms. Thus the moldedtriturate tablet preferably contains a medicament suitable for intraoraladministration in a dosage up to 30 mg and the molecular weight of thepharmaceutically active compound generally but not always does notexceed 350 daltons.

Another advantage of intraoral administration versus oral administrationis the avoidance of first pass metabolism. Generally a pharmaceuticalactive compounds for intraoral administration would have a lowerbioavailability if given by oral administration. One of the reasons forthe lower bioavailability for these orally administered pharmaceuticallyactive compounds is that they undergo presystemic metabolism/clearance(i.e. first pass metabolism). These active ingredients are metabolizedduring their first passage through the gut wall and liver and thereby asignificant fraction of the dose administered does not enter thebloodstream, and does not reach the receptors to exert activity. Attimes avoidance of presystemic metabolism results in avoiding themetabolism of the active drug into unwanted or aversive metabolites. Atother times it allows lower doses of the active drug to provide desiredactivity as compared to oral dosing. Additionally, the presence orabsence of food within the stomach and/or of the first portion of thesmall intestine may present erratic and/or unpredictable absorption ofcertain drugs. Thus the administration of medicament intraorally canavoid the food effect upon absorption.

The pharmaceutically active ingredients capable of intraoraladministration and the pharmaceutically active ingredients capable oforal administration may include analgesics, antihistamines,antidiarrheal, anxiolytic, hypnotics, stimulants, cardiovascular drugs,pulmonary drugs, anti-hypertensives, antiemetics, anti-inflammatorydrugs, renal drugs, steroids, drugs for neurological disorders,anticonvulsant drugs, drugs for treating endocrine disorders, drugs forsexual dysfunction, drugs for promoting immunology, drugs for treatingosteoarthritis, drugs for treating glaucoma, drugs for treating allergicrhinitis, drugs for treating anemias and other hematological disorders,drugs for treating infectious diseases, drugs for the treatment andsymptoms of cancer, drugs for insomnia, and antidiabetic drugs.

The pharmaceutically active ingredient capable of intraoraladministration must be capable of being absorbed sublingually orbuccally through mucous membranes of the oral cavity at itstherapeutically effective level. Such an active ingredient may have afirst pass metabolism that may be avoided by the intraoraladministration and preferably has a rapid onset through the intraoraladministration.

The pharmaceutically active ingredient capable of oral administrationand orally administered may be the same as or may be different from thepharmaceutically active ingredient that is capable of intraoraladministration and intraorally administered. The orally administeredpharmaceutically active ingredient may be formulated as a chewable orswallowable form for immediate, sustained or delayed release of thepharmaceutical active compound. The sustained release action of thepharmaceutical active compound may range from 0.5 to 12 hours. A delayedrelease of the pharmaceutical active compound may also be effected from0.5 to 12 hours after administration of the dosage unit.

The pharmaceutically active ingredient capable of oral administrationand orally administered may be the same or may be a differentpharmaceutically active ingredient from the intraorally administeredpharmaceutically active ingredient of the molded triturate tablet. Inthe situation when the orally administered active pharmaceuticalingredient is different from the intraoral active pharmaceuticalingredient, it is intended to provide therapeutic benefit such as therelief of different symptoms of the same disease or to synergisticallyincrease the total therapeutic effect of the individual pharmaceuticallyactive ingredients. Depending upon the pharmaceutical active ingredientselected and the desired therapeutic effect to be achieved, this newdosage form can be formulated to be administered as needed at any timeof the day or can be formulated for either morning (A.M.) or evening(P.M.) administration. For example, sedating and non-sedatingantihistamines may be formulated into a dosage unit of this invention sothat the sedating antihistamines, such as diphenhydramine orchlorpheniramine can be selected to be incorporated in the rapid releasetriturate portion and a non-sedating antihistamine such as loratadinemay be selected for delayed release compressed annular tablet portion.Administration of such a dosage unit at or prior to bedtime providesrapid release of the sedating antihistamine in the triturate portionhence providing antihistaminic activity and additionally utilizing itssedating properties to aid in the onset of sleep. The non-sedatingdelayed release compressed tablet containing loratadine may beformulated to release loratadine 4 to 8 hours after ingestion of thedosage unit and thus be available upon waking for A.M. and day timetherapeutic effect.

To summarize the features which can be unique for such a delivery systeminclude:

-   1. Versatility which provides both rapid absorption through    intraoral administration to avoid first pass metabolism as well as    prolonged and(or) sustained absorption through the sustained or    delayed release oral administration of the second portion.-   2. Pharmacological complementarity.-   3. Reduced dosage of the active ingredient by avoiding first pass    metabolism.-   4. Reduced side effects by avoiding the formation of undesired toxic    metabolites.-   5. P.M. or A.M. administration with clear advantages in terms of    delivering medicament for specified time of the day for desired    effect.-   6. Improved compliance by administering two doses of one or more    pharmaceutical active ingredient in one dosage form.

Examples of the pharmaceutically active ingredients capable of intraoraladministration that are known in the art, based on theirphysicochemical, pharmacokinetic and pharmacodynamic properties aremany. These active ingredients are not limited to those which include:

Buprenorphine, Butorphanol, Fenoprofen, Flurbiprofen, Diflunisal,Naproxen, Ibuprofen, Potassium Diclofenac, Fentanyl, Sodium Diclofenac,Parecoxib, Valdecoxib, Ketorolac, Tramadol, Bupropion, Aceclofenac,Acetaminophen, Acetanilide, Alphaprodine, Codeine, Dihydrocodeine,Dihydromorphine, Hydrocodone, Hydromorphone, Indoprofen, Ketoprofen,Ketorolac, Levorphanol, Loxoprofen, Meperidine, Methadone, Morphine,Naloxone, Pentazocine, Norlevorphanol, Oxycodone, Oxymorphone,Phenazocine, Propoxyphene, Tramadol, Zomepirac, Zolpidem, Zaleplon,Bupropion, Lorazepam, Buspirone, Ipsapirone, Gepirone, Triazolam,Nitrazepam, Estazolam, Diazepam, Oxazepam, Acetazolamide, Amiloride,Butazolamide, Clofenamide, Disulfamide, Ethacrynic Acid, Ethiazide,Ethoxzolamide, Etozolin, Fenquizone, Furosemide, Hydrochlorothiazide,Quinethazone, Torsemide, Triamterene, Cyproheptadine, Acravistine,Azatadine Maleate, Brompheniramine, Dextromethorphan, CarinoxamineMaleate, Chlorpheniramine, Descarboxyethyloratadine, Fexofenadine,Loratadine, Clemastine, Pseudoephedrine, Dexbrompheniramine,Diphenhydramine, Norastemizole, Doxylamine, Ketotifen, Promethazine,Tripelennamine, Plaunotol, Rosaprostol, Rotraxate, Spizofurone,Teprenone, Troxipide, Zolimidine, Temelastine, Naratriptan, Dizatriptan,Frovatriptan, Zolmitriptan, Sumatriptan, Almostriptan, Rizatriptan,Propanolol, Atenolol, Amitryptyline, Nortriptyline, Doxepin, Verapamil,Amlodipine, Ergotamine Tartrate, Caffeine, Dihydroergotamine, Bupropion,Methylphenidate, Captopril, Clonidine, Betaxolol, Bisoprolol,Nitroglycerin, Isorbide Mononitrate, Isosorbide Dinitrate, Bufuralol,Furosemide, Guanabenz, Guanfacine, Hydralazine, Labetalol, Metoprolol,Nadolol, Nifedipine, Oxprenolol, Pindolol, Sotalol, Timolol, Bunitrolol,Indecaimide, Nadoxolol, Penbutolol, Tocainide, Hydrochlorothiazide,Furosemide, Granisetron, Odansetron, Prochlorperazine, Metoclopramide,Clonazepam, Vigabatrin, Sildenafil, Alprostadil, Protriptyline,Trimiperamine, Imipramine, Desipramine, Azesetron, Batanopride,Zacopride, Bromopride, Acizapride.

To those skilled in the art, it is well known that physicochemicalproperties can be influenced by other inert agents which includepenetration enhancers, pH modifiers and other taste masking agents toenhance intraoral administration).

Examples of the pharmaceutically active ingredients capable of oraladministration not limited to but include: Bupropion, Rofecoxib,Fenoprofen, Flurbiprofen, Diflunisal, Naproxen, Ibuprofen, Indomethacin,Etodolac, Sulindac, Fentanyl, Sodium Diclofenac, Celecoxib, Parecoxib,Valdecoxib, Ketorolac, Tramadol, Aceclofenac, Acetanilide,Acetylsalcylsalicylic Acid, Alphaprodine, Aspirin, Bermoprofen,Naprosyn, Codeine, Dihydrocodeine, Dihydromorphine, Hydrocodone,Hydromorphone, Indoprofen, Ketoprofen, Ketorolac, Levorphanol,Loxoprofen, Mefenamic Acid, Meperidine, Methadone, Morphine, Nabumetone,Pentazocine, Norlevorphanol, Normethadone(N-desmethyl-methadone),Normorphine (N-desmethyl-morphine), Oxycodone, Oxymorphone, Phenazocine,Propoxyphene, Salsalate, Suprofen, Tramadol, Zomepirac, Zolpidem,Zaleplon, Zopiclone, Hydroxyzine, Trazodone, Citalopram, Lorazepam,Buspirone, Ipsapirone, Gepirone, Triazolam, Nitrazepam, Estazolam,Diazepam, Oxazepam, Acetazolamide, Amanozine, Amiloride,Benzylhydrochlorothiazide, Bumetanmide, Buthiazide, Chlorothiazide,Clofenamide, Clopamide, Clorexolone, Cyclothiazide, Disulfamide,Ethacrynic Acid, Ethiazide, Ethoxzolamide, Etozolin, Fenquizone,Furosemide, Hydracarbazine, Hydrochlorothiazide, Hydroflumethiazide,Indapamide, Mefruside, Methazolamide, Methyclothiazide, Metolazone,Pamabrom, Torsemide, Trimterene, Xipamide, Spironolactone,Cyproheptadine, Meclizine, Brompheniramine, Dextromethorphan,Citirizine, Chlorpheniramine, Descarboxyethyloratidine, Pexofenadine,Loratadine, Pseudoephedrine, Dexbrompheniramine, Diphenhydramine,Norastamizole, Doxylamine, Ketotifen, Promethazine, Tripelennamine,Cimedtidine, Famotidine, Lansoprazole, Nizatidine, Omeprazole,Pantoprazole, Pirenzepine, Plaunotol, Ranitidine, Rebamipide,Rioprostil, Roxatidine Acetate, Telenzepine, Troxipide, Zolmidine,O-Desmethyl astemizole, Acrivastine, Temelastine, Naratriptan,Dizatriptan, Zolmitriptan, Sumatriptan, Almotriptan, Eletriptan,Rizatriptan, Propanolol, Atenolol, Amitryptyline, Nortriptyline,Doxepin, Verapamil, Amlodipine, Ergotamine tartrate, Caffeine,Dihydroergotamine, Amoxapine, Bupropion, Citalopram, Clomipramine,Desipramine, Doxepin, Fluoxetine, Pluvoxamine, Paroxetine, Trazodone,Vanlafaxine, d-amphetamine, Captopril, Enalapril, Lisinopril, Quinapril,Acebutolol, Benzapril, Nitroglycerin, Isorbide Mononitrate, IsosorbideDinitrate, Bupranolol, Corvedilol, Condesortan, Diltiazem, Doxazosin,Felodipine, Fosinopril, Furosemide, Guanabenz, Guranfacine, Hydralazine,Indopamide, Irbesarton, Labetalol, Isradepine, Linopril, Losarton,Metolazone, Metoprolol, Mibefradil, Moexipril, Nadolol, Nicardipine,Nifedipine, Nisoldipine, Oxprenolol, Pindolol, Prazosin, Propranolol,Quinapril, Rampipril, Sotalol, Telmisartan, Temocapril, Terazosin,Trandolapril, Valsartan, Verapamil, Amiodarone, Aprindine, Bufetolol,Bunitrolol, Encainide, Flecainide, Indecaimide, Mexiletine, Nadoxolol,Penbutolol, Practolol, Propafenone, Quinidine Sulphate, Tocainide,Bumetamide, Loperamide, Granistron, Dolasetron Mesylate, Ondansetron,Dexamethasone, Prochlorperazine, Metoclopramide, Gabapenten,Carbamazepine, Clonazepam, Lamotrigine, Phenyloin, Tigabine, Vigabatrin,Sildenafil, Papaverine, Azesetron, Cleopride, Batanopride, Itopride,Zacopride, Bromopride, Acizapride.

Pharmaceutically acceptable acid salts of the pharmaceutically activeingredient capable of intraoral administration or of thepharmaceutically active ingredient capable of oral administration andcapable of forming pharmaceutically acceptable acid addition saltswithin the scope of this invention include the salts of anypharmaceutically acceptable inorganic acid or organic acid. Suchinorganic acids may include: hydrochloric, hydrobromic, sulfuric, nitricor phosphoric acid. The organic acids may include acetic, propionic,glycolic, lactic, propyruvic, malonic, succinic, methanesulfonic,ethanesulfonic, benzenesulfonic, salicylic, malic, tartaric, maleic,fumaric, adipic, citric, ascorbic or cinnamic acid. The drugs withacidic functional groups may also include pharmaceutically acceptablesalt-forming cations such as sodium, potassium or ammonium.

In the CAT/T for intraoral and oral administration the molded trituratetablet (T) contains a pharmaceutically active ingredient capable ofintraoral administration and the CAT contains a pharmaceutically activeingredient capable of oral administration. The resulting pharmaceuticalcomposition may be therapeutically effective over a duration of severalhours up to 24 hours, especially where the pharmaceutically activeingredient capable of oral administration contained in the CAT is insustained-release or delayed-release form.

Not only may the CAT contain an additional active ingredient capable oforal administration but furthermore the molded triturate tablet may alsocontain an additional pharmaceutically active ingredient capable ofintraoral administration. In fact the CAT and the triturate tablet mayboth contain additional pharmaceutically active agents.

The triturate tablet for intraoral administration may include one ormore pharmaceutically acceptable excipients such as but not limited tolactose, sucrose, dextrose, mannitol, starch, polyvinylpyrrolidone,microcrystalline, talc, sweeteners and flavoring agents. Other inertingredients that may be included in the triturate tablet includesolvents such as ethanol, polyethylene glycol, tetramethylene glycol,pentamethylene glycol, polyvinylpyrrolidones, mono-lower alkyl ethers ofdiethylene glycol and acetate esters of mono-lower alkyl ethers ofdiethylene glycol and purified water. The triturate blend may beprepared by mixing the pharmaceutical active ingredient(s) and thedesired excipients in ethanol and/or water mixture to form a semi-moistpowder mass.

The CAT may include, in addition to the pharmaceutically activeingredients capable of oral administration, pharmaceutically acceptableinert carriers such as, but not limited to, lactose, sucrose, dextrose,mannitol, microcrystalline cellulose, binding agents such as methylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, starch,acacia and other gums, glidants such as talc and colloidal silica,lubricant such as magnesium stearate and a flavoring agent. The CAT maycontain one or more excipients such as methylcellulose, hydroxypropylmethylcellulose, ethyl cellulose, cellulose acetate phthalate, acacia,gums, wax, glycerol monostearate, acrylic acid polymers and copolymers,methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate,ethyl methacrylate for sustained release formulations and one or moreingredients such as methylcellulose, hydroxypropyl cellulose,hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropylmethylcellulose, cellulose acetate succinate, ethylcellulose, celluloseacetate phthalate, cellulose acetate trimellitate, carboxymethylcellulose sodium, acrylic acid polymers and copolymers, methacrylicacid, methyl acrylate, ethyl acrylate, methyl methacrylate, ethylmethacrylate, polyvinylpyrrolidone, vinyl acetate, vinyl acetatephthalate, azo compounds, pectin, amylose, shellac, zein, and guar gumfor delayed release formulations.

In the manufacturing process, making the CAT is the essential first stepin fabricating the complete dosage unit. The desired ingredients in theCAT are blended to form a dry blend and compressed into an annulartablet or the blend may first be granulated with a binder solution suchas povidone in water, dried and milled to the desired particle size andthen blended with a glidant and/or lubricant and then compressed into anannular tablet. The blend may contain sustained release excipients whichmay then be compressed into a sustained release CAT. The CAT may containbeads or pellets that are made with or are coated with sustained ordelayed release material to sustain or delay the release of medicamentin the beads. The CAT may be compressed using commercial high-speedrotary tablet machines equipped with punches having core rods. Typicaltableting machines are Vector-Colton Model 216, Stokes/Pennwalt ModelB3B, Kiusui Models Hercules and others. The CAT may be further coatedwith a sustained or delayed release material to delay the release of thecontents of the compressed tablet. The CAT may also be applied with afilm-coat for additional protection of the tablet. The finished dosageform may be manufactured by feeding the compressed annular tabletthrough a transfer chute which places the CAT onto the rotary drivenmolding plate of the tablet triturate machine and the CAT falls into thecavity of the plate. The CAT which is now inserted into the moldingplate provides the annular mold for the triturate to be formed. Atypical automated triturate machine such as the Vector Model 820 can beemployed with modification to feed the CAT into the molding plate. Ingeneral, an automatic triturate machine includes a power feed stationwhich supplies the triturate blend, a semi-wet powder, to the topsurface of the molding plate. A tablet molding station provides forcontinuously spreading the semi-moist powder into the feed stationhousing the compressed annular tablet. The moist mass is pressed intothe annuli of the CAT. An ejector station has lower punches which movethe tablet molding plate so as to eject the CAT/T onto a conveyer wherethey are removed from the machine. The CAT/T should preferably be a flatfaced tablet and suitable in size to be placed comfortably intraorally.The size of the CAT/T may vary depending on the drugs and doses to beadministered. The outer diameter of the compressed annular tablet mayrange from ¼″ to 1″ and more preferably {fraction (9/32)}″ to ¾″ andmore preferably {fraction (5/16)}″ to ½″. The diameter of the moldedtriturate tablet is dependent upon the diameter of the center cavity ofthe CAT and may range from a size of {fraction (7/16)}″ or smaller morepreferably ¼″ or smaller but minimally greater than 0.1″. The thicknessof the CAT/T will be approximately {fraction (1/10)}″ or greater.

The dosage form is formulated so that the triturate disintegratesrapidly within 10 minutes and the patient is then instructed to chew orswallow the remainder of the dosage unit. The second portion of thecomposition, CAT which contains the pharmaceutically active ingredientcapable of oral administration remains substantially intact and does notdissolve or disintegrate while the pharmaceutically active ingredientcapable of intraoral administration is intraorally administered.

The invention further comprises a method of administering apharmaceutical composition in unit dosage form for both intraoral andoral administration to a patient, which comprises:

-   -   (a) as a first releasing portion, a molded triturate tablet        comprising a therapeutically effective amount of at least one        pharmaceutically active ingredient capable of intraoral        administration; and as a second portion located around the        triturate tablet as a CAT, a therapeutically effective amount of        at least one pharmaceutically active ingredient capable of oral        administration and which is releasable and orally ingestible by        the patient after the molded triturate tablet has disintegrated        or has dissolved intraorally, comprising the steps of:        -   (i) placing the pharmaceutical dosage unit CAT/T            intraorally;        -   (ii) retaining the pharmaceutical dosage CAT/T intraorally            until the first portion, the molded triturate tablet            containing the pharmaceutically active ingredient capable of            intraoral administration has disintegrated or dissolved            thereby substantially releasing the pharmaceutically active            ingredient for intraoral absorption; and        -   (iii) following step (ii) swallowing whole or chewing and            swallowing the remaining dosage unit.

According to one feature of the invention the first portion of thecompositions, the triturate tablet which contains the pharmaceuticallyactive ingredient capable of intraoral administration disintegratesand/or dissolves rapidly, within 10 minutes, or shortly after thecomposition comes into contact with the patient's saliva. The secondportion of the composition, CAT which contains the pharmaceuticallyactive ingredient capable of oral administration remains substantiallyintact and does not dissolve or disintegrate while the pharmaceuticallyactive ingredient capable of intraoral administration is intraorallyadministered.

Where it is desired to allow a rapid mucosal absorption of thepharmaceutically active ingredient capable of intraoral administration,the molded triturate tablet in the first portion containing thepharmaceutically active ingredient capable of intraoral administrationwill dissolve or disintegrate substantially immediately.

Once the triturate tablet in the first portion has dissolved ordisintegrated, the second portion of the composition is either swallowedwhole or chewed by the patient to release the pharmaceutically activeingredient capable of oral administration.

The present invention also relates to a process for the preparation of apharmaceutical composition in unit dosage form as a CAT/T for bothintraoral and oral administration to a patient, said pharmaceuticalcomposition placed intraorally in said patient, which comprises:

-   -   (a) as a first release portion, at least one discrete molded        triturate tablet comprising a therapeutically effective amount        of at least one pharmaceutically active ingredient capable of        intraoral administration; and    -   (b) as a second portion located around the said first portion, a        therapeutically effective amount of at least one        pharmaceutically active ingredient capable of oral        administration and which is releasable and orally ingestible by        the patient after the triturate tablet has disintegrated or has        dissolved intraorally. The preparation of the dosage unit        comprises the steps of:        -   (i) preparing a triturate blend of pharmaceutically active            ingredient and excipient blend which is moistened with            ethanol or water or the mixture of;        -   (ii) preparing the second portion as a compressed annular            tablet of at least one layer or a multi-layer CAT; and        -   (iii) molding the first portion as a triturate tablet into            the CAT.

The CAT unit may be coated prior to the molding of the triturate. Thecoating could be a film coat that is applied to the CAT. The film coatmay comprise pharmaceutically acceptable coating polymers selected fromthe group consisting of cellulose, hydroxypropyl methylcellulose, methylcellulose, polyvinylpyrrolidone, and polyethylene glycol, apharmaceutically acceptable plasticizer, a pharmaceutically acceptableglidant and a pharmaceutically acceptable flavoring agent.

The molded triturate tablet comprises the pharmaceutically activecompound for intraoral administration and is formulated with at leastone pharmaceutically acceptable excipient for intraoral administrationsuch as lactose, sugar, dextrose, mannitol, sorbitol, microcrystallinecellulose, starch, sodium starch glycolate, polyvinylpyrrolidone,polyethylene glycol, and magnesium stearate, talc, or a flavoringagents. Other inert ingredients that may be used in the inlaid triturateunit include solvents such as ethanol, polyethylene glycol,tetramethylene glycol, pentamethylene glycol, polyvinylpyrrolidones,mono-lower alkyl ethers of diethylene glycol and acetate esters ofmonolower alkyl ethers of diethylene glycol, or purified water.

Alternatively the molded triturate tablet comprising at least onepharmaceutically active ingredient capable of intraoral administrationmay contain at least one pharmaceutically acceptable effervescent agentsuch as an alkali carbonate or bicarbonate capable of renderingeffervescence when contacted with water.

In any of the compositions disclosed herein above the molded trituratetablet may contain a pharmaceutically acceptable flavoring or tastemasking agent. The CAT in one feature of the present invention is animmediate drug release tablet.

Preferably the immediate release CAT comprises the pharmaceuticallyactive ingredient capable of oral administration and is formulated witha conventional pharmaceutically acceptable excipient for oraladministration such as lactose, sugar, mannitol, sorbitol, calciumsulfate, calcium phosphate dibasic, microcrystalline cellulose,methylcellulose, starch, sodium starch glycolate, polyvinylpyrrolidone,polyethylene glycol talc and magnesium stearate. The CAT may compriseone or more layers and where the CAT comprises multiple layers, one ormore of the layers may contain the pharmaceutically active ingredientcapable of oral administration in immediate release form.

In another feature of the present invention the CAT is a sustained drugrelease tablet which provides sustained release of the pharmaceuticallyactive ingredient capable of oral administration. Preferably thesustained release effect lasts for 0.5 to 24 hours. The sustained drugrelease CAT comprises the pharmaceutically active ingredient capable oforal administration and is formulated with conventional pharmaceuticallyacceptable excipients for oral administration in sustained drug releaseform such as methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, cellulose acetate phthalate, acacia, gums, wax, glycerolmonostearate, acrylic acid polymers and copolymers, methacrylic acid,methyl acrylate, ethyl acrylate, methyl methacrylate, ethylmethacrylate, and one or more conventional pharmaceutical excipients fororal administration such as lactose, calcium sulfate, calcium phosphatedibasic, sugar, microcrystalline cellulose, starch, sodium starchglycolate, polyvinylpyrrolidone, polyethylene glycol and magnesiumstearate. In addition to formulating with the above sustained releaseexcipients, the CAT may also be prepared with ion-exchange resins toform a sustained release complex. The CAT may comprise one or morelayers. When the compressed tablet comprises multiple layers, one ormore of the layers may contain the pharmaceutically active ingredientcapable of oral administration in sustained release form.

In addition to pharmaceutical compositions where the CAT contains thepharmaceutically active ingredient capable of oral administration is inimmediate release form or sustained release form, it is also within thescope of the invention that compositions of the CAT are coated with adelayed release coating, preferably delaying the release of medicamentfor 0.5 to 12 hours. The delayed release coating may be formulated withone or more pharmaceutically acceptable polymers selected from the groupconsisting of methylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose,cellulose acetate succinate, ethylcellulose, cellulose acetatephthalate, cellulose acetate trimellitate, carboxymethyl cellulosesodium, acrylic acid polymers and copolymers, methacrylic acid, methylacrylate, ethyl acrylate, methyl methacrylate, ethyl methacrylate,polyvinylpyrrolidone, vinyl acetate, vinyl acetate phthalate, azocompounds, pectin, amylose, shellac, zein, and guar gum, in combinationwith a pharmaceutically acceptable plasticizer and a glidant. Thepharmaceutical active ingredient may be formulated in beads or pelletsand then enteric-coated with enteric coating polymers as describedabove. The enteric-coated beads or pellets may then be blended withother excipients and compressed into the CAT.

The CAT containing the pharmaceutically active ingredient capable oforal administration may be sucked, swallowed whole by the patient or maybe in chewable form. The CAT may consist of multiple layers containingone or more pharmaceutically active ingredient capable of oraladministration and may be in a chewable form. The CAT in chewable formor the CAT with multiple layers in chewable form comprises thepharmaceutically active ingredient capable of oral administration and apharmaceutically acceptable excipient for chewable tablets selected fromthe group consisting of lactose, sorbitol, mannitol, sugar, starch,citric acid, tartaric acid, sweetening agent, magnesium stearate, andoptionally with a flavoring agent.

The unique features of the delivery system of the invention includespharmacological complementary, reduced side effects and versatilitywhich provide immediate as well as sustained and prolonged therapeuticbenefits along with improved patient compliance. For example, a patientwith angina pectoris due to coronary artery disease may benefit fromthis dosage form, when the triturate provides immediate onset ofactivity from intraoral nitroglycerin for acute relief and prophylaxisin life threatening situations of an acute angina attack and subsequentially the availability of oral delayed isorbide mononitratesustained release for angina pectoris prevention. This provides thepatient immediate relief from the acute angina attack and at the sametime the benefit of continued prevention from angina pectoris up toapproximately 12 hours.

BRIEF DESCRIPTION OF THE DRAWING

The sole FIGURE in this application is a perspective drawing cut insection and which shows the tablet.

DETAILED DESCRIPTION OF THE DRAWING

The drawing shows the compressed tablet with a central cavity and aninlaid triturate where the first portion—which is an inlaid triturate 1suitable for intraoral administration. The 5 second portion 2, suitablefor oral administration, comprises a compressed tablet with a centralcavity which surrounds the inlaid triturate.

An important feature of this dosage form is that the disintegration ofthe molded triturate tablet signals the patient to swallow the remainingportion, the CAT, or after a specified time the patient is instructed toswallow or chew the CAT and thus the CAT is administered just as anyconventional oral medication once the molded triturate hasdisintegrated.

It is common to add a flavoring agent to a medicament that isintraorally administered. The molded triturate may contain such aflavoring agent dispersed throughout to make the intraoraladministration more pleasant to the patient. Where there is such aflavoring agent in the molded triturate, there may the same or differentflavor in CAT.

Compressed Annular Tablet with Molded Triturate Tablet, CAT/T.

EXAMPLES Example 1 Anti-migraine Agent—Zolmitriptan 1.25 to 2.5 mgImmediate Release and Zolmitriptan 1.25 to 2.5 mg in Delayed Release

(A) Preparation of Zolmitriptan CAT:

(a) Preparation of Zolmitriptan beads:

Typical Example Ingredients % Weight mg/unit Zolmitriptan  1-10 1.25Talc 0.1-5   0.12 Polyvinylpyrrolidone 0.1-5   0.12 Water/ethanol (To beevaporated) (To be evaporated) Sugar spheres 80-98 60 Sub Total 61.49Procedure:

-   (1) Prepare a dispersion containing Zolmitriptan and talc in    polyvinylpyrrolidone solution prepared in water and/or ethanol or a    mixture thereof.-   (2) Apply or spray solution (1) onto the sugar spheres using a    coating pan or a fluid bed coater until a desired amount of    solution (1) is applied.-   (3) The coated spheres may be further seal-coated with a solution    containing polyvinylpyrrolidone prepared in water and/or ethanol or    a mixture thereof.    (b) Preparation of Enteric Coated Zolmitriptan beads:

Typical Example Ingredients % Weight mg/unit Eudragit S100  2-15 6.0Triethyl citrate 1-7 3.0 Talc 0.5-4   1.5 Ammonium (As 1N (3.5%)0.05-0.3  0.105 ammonium hydroxide (3.0 ml 1N Solution) solution) Water(To be evaporated) (To be evaporated) Zolmitriptan beads 70-95 61.49(step (a)) Sub Total 72.09Procedure:

-   (1) Prepare the coating solution by mixing water, Eudragit S100,    ammonium hydroxide solution, triethyl citrate and talc to form a    uniform dispersion.-   (2) Coat Zolmitriptan beads (from (a)) with Eudragit S coating    solution using a coating pan or a fluid bed coater until a desired    coat weight is achieved.    (c) Seal Coat of the Enteric Coated Zolmitriptan Beads:

Typical Example Ingredients % Weight mg/unit Hydroxypropyl  2-15 3.1methylcellulose Polyethylene glycol 0.2-4   0.4 Optional Flavoring0.2-5   0.5 agent Optional coloring 0.2-5   0.5 agent Water or ethanol(To be evaporated) (To be evaporated) Zolmitriptan Enteric 85-97 72.09Coated beads (step b) Sub Total 76.59Procedure:

-   (1) Prepare a coating solution of Hydroxypropyl methylcellulose and    polyethylene glycol in water or ethanol or combination thereof.-   (2) Coat Zolmitriptan Enteric Coated beads (step (b)) with the above    coating solution in a coating pan or a fluid bed coater until a    desired coating weight is obtained.    (d) Preparation of Zolmitriptan CAT:

Typical Example Ingredients % Weight mg/unit Lactose monohydrate 20-60100 Microcrystalline 15-35 60 cellulose Polyvinylpyrrolidone  2-10 10Flavoring agent(s) 0.5-5   5 Magnesium Stearate 0.2-2.0 1.0 ZolmitriptanEnteric 20-50 76.59 Coated beads (step c) Sub Total 253.59Procedure:

-   (1) Prepare a granulation blend of lactose, microcrystalline    cellulose, polyvinylpyrrolidone and flavoring agent. Blend with    Zolmitriptan Enteric Coated beads (step (c)) and final blend with    magnesium stearate.-   (2) Compress the granulation blend into a CAT using compression    tooling and tabletting apparatuses.    (B) Preparation of Zolmitriptan triturate blend:

Typical Example Ingredients % Weight mg/unit Zolmitriptan 1-5 1.25Lactose, fine powder 50-90 55 Sucrose, fine powder 10-40 10 Flavoringagent 0.5-5   1 Polyvinylpyrrolidone 0.05-1   0.05 Ethyl alcohol, 95%(To be evaporated) — Water (To be evaporated) — Sub Total 67.3Procedure:

-   (1) Prepare the solvent mixture containing polyvinylpyrrolidone,    ethyl alcohol and water.-   (2) Blend Zolmitriptan, lactose, sucrose and the flavoring agent.    Screen to break lumps.-   (3) Add (1) to (2) while mixing until a moistened powder blend is    achieved.    (C) Preparation of molded triturate into the CAT/T The finished    product (CAT/T)

Typical Example Ingredients CAT % Weight mg/tablet Zolmitriptan (A)70-90 253.59 Zolmitriptan Triturate Blend (B) 10-30 67.3 Total (Finishedproduct) 310.89Procedure:

-   (1) Prepare the finished dosage form by triturating (B) into the    center hole of the CAT (A) using an apparatus capable of molding    triturate into the center cavity of the CAT.    (D) Description of the Finished Dosage Design (CAT/T)

The product contains 1.25 mg Zolmitriptan in the molded triturate tabletfor intraoral release and 1.25 mg Zolmitriptan in the delayed releasebeads which are incorporated in the matrix of CAT unit. Enteric coatedZolmitriptan starts to release 2 to 4 hours after oral administration ofthe dosage form. The patient is instructed to take the dosage unit(CAT/T) intraorally where the molded triturate tablet disintegratesrapidly resulting in the release of the drug for rapid intraoralabsorption. Once the disintegration of triturate tablet is complete thepatient may swallow the remainder of the dosage unit, the CAT, whichwill then releases the second part of the medicine 2-4 hours afteradministration of the dosage unit. The dosage form provides initialrapid onset of Zolmitriptan from the triturate tablet portion of thedosage unit and also provide a second dose of Zolmitriptan 2 to 4 hoursafter the dosage administration for a total of about 4 to 5 hourstreatment in migraine headaches.

Example 2 Antiemetic and Narcotic Formulation—Granisetron Hydrochloride1.12 mg (equivalent to 1 mg base) for Intraoral Administration andMorphine Sulfate 30 to 120 mg in Sustained Release for OralAdministration

(A) Preparation of Morphine sulfate sustained release CAT:

Typical Example Ingredients % Weight mg/unit Morphine sulfate 10-25 30Hydroxypropyl Methylcellulose 45-65 130  Lactose monohydrate 20-40 70Polyvinylpyrrolidone  3-10 10 Silicone dioxide 0.3-1.5  2 Stearic acid0.3-1.5  2 Sub Total 244 Procedure:

-   (1) Prepare a granulation blend containing Morphine sulfate,    hyproxypropyl methylcellulose, lactose and polyvinylpyrrolidone. Add    silicon dioxide and stearic acid to the granulation and blend for    additional 5 to 10 minutes.-   (2) Compress the above Morphine sulfate sustained release    granulation into CAT unit using appropriate tooling and tabletting    apparatuses.    (B) Preparation of Granisetron Triturate Blend

Typical Example Ingredients % Weight mg/unit Granisetron hydrochloride1-5 1.12 Lactose, fine powder 60-95 60 Sucrose, fine powder  5-20 5Flavoring agent 0.5-5   1 Polyvinylpyrrolidone 0.05-1   0.06 Ethylalcohol, 95% (To be evaporated) — Water (To be evaporated) — Sub Total67.18Procedure:

-   (1) Prepare the solvent mixture containing polyvinylpyrrolidone in    water or a mixture of water and ethanol.-   (2) Blend Granisetron hydrochloride, lactose, sucrose and the    flavoring agent. Screen to break lumps.-   (3) Add (1) to (2) while mixing until a moistened powder blend is    achieved.    (C) Preparation of Molded Triturate Tablet into the CAT—the Finished    Product CAT/T

Typical Example Ingredients % Weight mg/tablet Morphine sulfatesustained release 70-90 244 CTCC (A) Granisetron Triturate Blend (B)10-30 67.18 Total (Finished product) 311.18Procedure:Prepare the finished dosage form by pressing the semi-moist triturateblend (B) into the center cavity of the CAT (A) using suitable equipmentcapable of molding triturate tablets into the center cavity of a CAT.(D) Description of the Dosage Unit Design:

The product contains 1.12 mg Granisetron hydrochloride in the moldedtriturate tablet for intraoral release and 30 mg morphine sulfate in thematrix of CAT unit as a sustained release form which releases morphinefor a period of 8 to 12 hours. The patient is instructed to take thedosage unit (CAT/T) intraorally where the molded triturate tabletdisintegrates rapidly resulting in the release of Granisetron for rapidintraoral absorption. Once the disintegration of molded triturate tabletis complete the patient may swallow the remainder of the dosage unit,the CAT, which will then release morphine in a sustained release for 8to 12 hours. Nausea and vomiting is a common adverse reaction associatedwith administration of morphine and other narcotic analgesics. Theadministration of an antiemetic agent such as Granisetron prior to theadministration of a narcotic analgesic prevents the nausea and vomitingside effects.

Example 3 Sedating and Non-sedating Antihistamine—ChloropheniramineMaleate 2 to 4 mg for Intraoral Administration and Loratadine 5 to 7 mgin Delayed Release Form for Oral Administration

(A) Preparation of Loratadine CAT:

Typical Example Ingredients % Weight mg/unit Loratadine 2-5 5 Lactosemonohydrate 60-70 141.5 Microcrystalline cellulose 25 55 Starch 10 22Magnesium stearate 0.5 1.5 Sub Total 225Procedure:

-   (1) Prepare a granulation containing Loratadine, lactose,    Microcrystalline cellulose and starch.-   (2) Blend with magnesium stearate for 5 minutes.-   (3) Compress the above granulation into CAT unit using tooling and    tabletting apparatuses.    (B) Preparation of Enteric Coated Loratadine CAT:

Typical Example Ingredients % Weight mg/unit Eudragit S100  4-12 18Triethyl citrate 1-6 9 Talc 0.5-5   4.5 Ammonium (As 1N (3.5%) 0.05-0.5 0.315 ammonium hydroxide (9 ml 1N solution) solution) Water (To beevaporated) (To be evaporated) Loratadine CTCC (step 80-97 225 (A)) SubTotal 256.8Procedure:

-   (1) Prepare the coating solution by mixing water, Eudragit S100,    ammonium hydroxide solution, triethyl citrate and talc to form a    uniform dispersion.-   (2) Coat Loratadine CAT unit (from (A)) with Eudragit S coating    solution using a coating pan or a fluid bed coater until a desired    coat weight is achieved.    (C) Seal Coat of the Enteric Coated Loratadine CAT Unit:

Typical Example Ingredients % Weight mg/unit Eudragit EPO  2-15 14.0Citric acid 1-6 8 Water (To be evaporated) (To be evaporated) LoratadineEnteric 90-98 256.8 Coated CTCC (step (B)) Sub Total 278.8Procedure:

-   (1) Prepare a coating solution containing Eudragit E and citric acid    in water.-   (2) Coat Loratadine Enteric Coated CAT unit (step (B)) with the    above coating solution in a coating pan or a fluid bed coater until    a desired coating weight is obtained.    (D) Preparation of Chloropheniramine Maleate Triturate Blend:

Typical Example Ingredients % Weight mg/unit Chloropheniramine 1-5 4maleate Lactose, fine powder 50-90 45 Sucrose, fine powder 10-40 15Flavoring agent 0.5-5   2 Polyvinylpyrrolidone 0.05-1   0.1 Ethylalcohol, 95% (To be evaporated) (To be evaporated) Water (To beevaporated) (To be evaporated) Sub Total 66.1Procedure:

-   (1) Prepare the solvent mixture containing polyvinylpyrrolidone,    ethyl alcohol and water.-   (2) Blend Chloropheniramine maleate, lactose, sucrose and flavoring    agent. Screen to break lumps.-   (3) Add (1) to (2) until a moistened powder blend is achieved.    (E) Preparation of Molded Triturate into the CAT—the Finished    Product (CAT/T)

Typical Example Ingredients % Weight mg/tablet Loratadine enteric coatedCTCC (C) 70-90 278.8 Chloropheniramine maleate Triturate 10-30 66.1Blend (D) Total (Finished product) 344.9Procedure:Prepare the finished dosage form by pressing the semi-moist triturateblend (D) into the center cavity of the CAT (C) using an apparatuscapable of molding triturate tablets into the center of the CAT.(F) Description of the Dosage Unit Design (CAT/T):

The product contains 4 mg of Chloropheniramine maleate in the moldedtriturate tablet for intraoral release and 5 mg of Loratadine in thedelayed release form as incorporated in the matrix of CAT. Entericcoated Loratadine starts to release 4 to 8 hours after administration ofthe dosage form.

The patient is instructed to take the dosage unit intraorally where themolded triturate tablet disintegrates rapidly resulting in the releaseof chlorpheniramine maleate for rapid intraoral absorption. Once thedisintegration of the triturate tablet is complete the patient mayswallow the remainder of the dosage unit, the CAT, which will thenrelease the second part, loratadine, 4 to 8 hours after administrationof the dosage unit. The patient is instructed to take the antihistaminedosage form in the evening prior to bedtime. As a result of the dosagedesign, the sedating antihistamine is released substantially immediatelythrough intraoral administration for providing night time antihistamineactivity and sedation and the non-sedating antihistamine will bereleased 4 to 8 hours later for day time antihistaminic activity.

Example 4 Anti-Angina Formulation—Nitroglycerin 0.3 to 0.6 mg forIntraoral Administration and Isosorbide Mononitrate 30 to 120 mg inSustained Release for Oral Administration

(A) Preparation of Isosorbide Mononitrate Sustained Release CAT

Typical Example Ingredients % Weight mg/unit Isosorbide mononitrate10-25 30 Hydroxypropyl Methylcellulose 30-60 100  Lactose monohydrate10-25 40 Ethylcellulose 10-25 40 Polyvinylpyrrolidone  5-15 18 Siliconedioxide 0.3-1.5  2 Stearic acid 0.3-1.5  2 Magnesium stearate 0.1-1.0  1Sub Total 233 Procedure:

-   (1) Blend Isosorbide Mononitrate, hyproxypropyl methylcellulose,    ethylcellulose and lactose to form a uniform blend.-   (2) Prepare polyvinylpyrrolidone in water or a mixture of water and    ethanol solution.-   (3) Granulate step (1) with solution from step (2). Dry the    Granulation and screen or mill to desired particle size.-   (4) Add silicon dioxide, stearic acid and magnesium stearate and    blend for additional 5 to 10 minutes.    Compress Isosorbide sustained release CAT unit using tooling and    tabletting apparatuses.    (B) Preparation of Delayed Release Isosorbide CAT

Typical Example Ingredients % Weight Mg/tablet Eudragit L 100-55 3-8 18Triethyl citrate 0.3-2   1.8 Talc 0.5-3   4.5 Polyethylene glycol 60000.2-2   1.47 Sodium hydroxide 0.05-0.2  0.29 Water (To be evaporated) —Isosorbide mononitrate CTCC 85-98 233 (A) Sub Total 259.06Procedure:

-   (1) Prepare the coating solution by mixing water, Eudragit L 100-55,    Sodium hydroxide, PEG 6000, triethyl citrate and talc to form a    uniform dispersion.-   (2) Coat Isosorbide Mononitrate CAT (from (A)) with Eudragit L    coating solution using a coating pan or a fluid bed coater until a    desired coat weight is achieved.    (C) Seal Coat of the Enteric Coated Isosorbide CAT:

Typical Example Ingredients % Weight mg/unit Eudragit EPO  2-15 14.0Citric acid 1-6 8.0 Water (To be evaporated) (To be evaporated)Isosorbide mononitrate 90-98 259.06 Enteric Coated CAT (step (B)) SubTotal 281.06Procedure:

-   (1) Prepare a coating solution containing Eudragit E and citric acid    in water.-   (2) Coat Isosorbide Mononitrate Enteric Coated CAT unit (step (B))    with the above coating solution in a coating pan or a fluid bed    coater until a desired coating weight is obtained.    (D) Preparation of Nitroglycerin Semi-moist Triturate Blend:

Typical Example Ingredients % Weight mg/tablet Nitroglycerin 0.2-5   0.3Lactose, fine powder 70-95 65 Sucrose, fine powder  2-20 5 Flavoringagent 0.5-5   2 Polyvinylpyrrolidone 0.05-1   0.1 Ethyl alcohol, 95% (Tobe evaporated) — Water (To be evaporated) — Sub Total 72.4Procedure:

-   (1) Prepare the solvent mixture containing polyvinylpyrrolidone,    ethyl alcohol and water.-   (2) Blend Nitroglycerin, lactose, sucrose and the flavoring agent.    Screen to break lumps.-   (3) Add (1) to (2) until a moistened powder blend is achieved.    (E) Preparation of Molded Triturate Tablet into the CAT—the Finished    Product (CAT/T)

Typical Example Ingredients % Weight mg/tablet Isosorbide mononitrateEnteric 70-90 281.06 Coated Sustained release CTCC (B) NitroglycerinTriturate Blend 10-30 72.4 (C) Total (Finished product) 353.46Procedure:Prepare the finished dosage form by pressing the semi-moist triturateblend (C) into the center cavity of the CAT(B) using an apparatuscapable of molding triturate tablets into a CAT.(F) Description of the Dosage Unit Design:

The product contains 0.3 mg nitroglycerin in the molded triturate tabletfor intraoral release and 30 mg Isosorbide Mononitrate in the CAT as asustained release form which releases Isosorbide for a duration of 8 to12 hours. The Isosorbide sustained release CAT unit is further coatedwith delayed release formulation so that the sustained releasedIsosorbide CAT starts to release 1 to 2 hours after administration ofthe dosage form.

The patient is instructed to take the dosage unit intraorally where themolded triturate tablet disintegrates rapidly resulting in the rapidrelease of the drug for intraoral absorption. Once the disintegration ofmolded triturate tablet is complete the patient may swallow theremainder of the dosage unit, the CAT, which will then releaseIsosorbide Mononitrate 1 to 2 hours later for a sustained releaseduration of 8 to 12 hours. The initial immediate release ofNitroglycerin from the triturate provides a rapid onset to prevent acuteangina attack due to coronary artery disease for a duration of about 30minutes to 1 hour at which time the delayed and sustained releaseIsosorbide Mononitrate CAT starts to release and provides a duration of8 to 12 hours therapeutic intervention for prophylactic effect forangina.

REFERENCES

-   1. USP#5407339, Triturate Tablet Machine. Fehlhafer, J. E. April    18., 1995.-   2. USP#3873727, Stabilization of molded sublingual nitroglycerin    tablets. Fusari, S. A. Mar. 25, 1975.-   3. USP#5739136, Intraoral dosing method of administering    medicaments. Ellinwood Jr. Apr. 14, 1998.-   4. USP#4229447, Intraoral methods of using benzodiazepines. W. R.    Porter. Oct. 21, 1980.-   5. USP#6,183,778, Pharmaceutical tablet capable of liberating. one    or more drugs at different release rates. Conte, et al. Feb. 6, 2001-   6. USP#4,004,036, Effervescent molded triturate tablets. Schmitt.    Jan. 18, 1977.-   7. AHFS Drug Information 2000.-   8. Mosby's GenRx, 11th Ed. (2001).-   9. USP DI Vol. I—Drug Info. For the Health Care Pro., 21st Ed.    (2001).-   10. USP DI Vol. II—Advice for the Patient, 21st Ed. (2001). 11.    Ellenhorn's Medical Toxicology, 2nd Ed. (1994).-   12. Griffith's 5 Minute Clinical Consult., 9th Ed (2001). 13. The    Merck Manual, 17th Ed. (1999).-   14. Current Diagnosis & Treatment in Cardiology, 1st Ed. (1995).-   15. Current Critical Care Diagnosis & Treatment, 1st Ed. (1994).-   16. Textbook of Organic Medicinal & Pharmaceutical Chemistry, 10th    Ed. 1998-   17. The Complete Drug Reference, Martindale, 32nd Ed. 1999. 18. The    Merck Index, 12th Ed. 1996.-   19. Pharmacotherapy A Pathosphysiologic Approach, 4th Ed. 1999.-   20. Pharmacology, 2nd Ed. Lippincott's Illustrated Reviews. 1997.

1. A pharmaceutical composition which comprises: (a) an intraorallyreleasing first portion, in the form of a molded triturate tabletcomprising a therapeutically effective amount of at lease onepharmaceutically active ingredient capable of intraoral administrationhaving a molecular weight of less than 350, in a dosage of no more thanabout 50 mg, wherein the molded triturate tablet comprises an excipientand disintegrates or dissolves within 10 minutes permitting rapidrelease of the pharmaceutically active ingredient; and (b) a secondreleasing portion located around the first portion as a compressedannular tablet, comprising a therapeutic ingredient capable of oraladministration and which is releasable and orally ingestible by thepatient after the molded triturate has disintegrated or has dissolvedintraorally.
 2. The pharmaceutical composition defined in claim 1wherein the compressed annular tablet is comprised of one or more layerscontaining the pharmaceutically active ingredient capable of oraladministration.
 3. The pharmaceutical composition defined in clam 1wherein the molded triturate tablet contains a therapeutically effectiveamount of at least one pharmaceutically active ingredient capable ofintraoral administration and one or more pharmaceutically acceptableexcipients for intraoral administration.
 4. The pharmaceuticalcomposition defined in claim 1, wherein the molded triturate tablet isformulated with a pharmaceutically acceptable effervescent agent capableof generating effervescence when contacted with saliva.
 5. Thepharmaceutical composition as defined in claim 1 where the compressedannular tablet is film coated and contains a pharmaceutically acceptableflavoring agent.
 6. The pharmaceutical composition defined in claim 2wherein the compressed annular tablet is an immediate drug releasetablet comprising at least one pharmaceutically active ingredientcapable of oral administration and one or more pharmaceuticallyacceptable excipients for oral administration.
 7. The pharmaceuticalcomposition defined in claim 2 wherein the compressed annular tabletcomprises more than one layer including a sustained release layercontaining a therapeutically effective amount of a firstpharmaceutically active ingredient capable of oral administration andoptionally including an immediate release layer containing atherapeutically effective amount of a second pharmaceutically activeingredient capable of oral administration, same or different from thefirst.
 8. The pharmaceutical composition defined in claim 2 wherein thecompressed annular tablet comprises more than one layer comprising thepharmaceutically active ingredient capable of oral administration andwhere at least one of the layers comprising the pharmaceutically activeingredient capable of oral administration is an immediate drug releaselayer.
 9. The pharmaceutical composition defined in claim 7 where thecompressed annular tablet provides sustained release of thepharmaceutical active ingredient capable of oral administration for aperiod of 0.5 to 24 hours.
 10. The pharmaceutical composition defined inclaim 9 wherein the compressed annular tablet is formulated byincorporating or coating the pharmaceutically active ingredient with oneor more pharmaceutically acceptable sustained released polymers.
 11. Thepharmaceutical composition defined in claim 10 wherein the one or morepharmaceutically acceptable sustained release polymer is selected fromthe group consisting of methylcellulose, hydroxypropyl methylcellulose,ethyl cellulose, cellulose acetate phthalate, acacia, gums, wax,glycerol monostearate, acrylic acid polymers and copolymers, methacrylicacid, methyl acrylate, ethyl acrylate, methyl methacrylate, ethylmethacrylate, and ion exchange resins capable of forming a sustainedrelease ion-exchange resin-drug complex.
 12. The pharmaceuticalcomposition defined in claim 2 wherein the compressed annular tabletcomprises a therapeutically effective amount of one or morepharmaceutically active ingredients capable of oral administration in adelayed release form which delays the release of the one or morepharmaceutically active ingredients capable of oral administration for aperiod of 0.5 to 12 hours.
 13. The pharmaceutical composition defined inclaim 12 wherein the compressed annular tablet comprising atherapeutically effective amount of one or more pharmaceutically activeingredients capable of oral administration in a delayed release formincludes a delayed release coating on the one or more pharmaceuticallyactive ingredients, said delayed release coating comprising one or morepharmaceutically acceptable polymers selected from the group consistingof methylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxymethyl cellulose, hydroxypropyl cellulose acetatesuccinate, ethyl cellulose, cellulose acetate phthalate, celluloseacetate trimellitate, carboxymethylcellulose sodium, acrylic acidpolymers and copolymers, polymers or copolymers of methacrylic acid,methyl acrylate, ethyl acrylate, methyl methacrylate, ethylmethacrylate, vinyl acetate, vinyl acetate phthalate, an azo compound,polyvinyl pyrrolidone, pectin amylose, shelac, zein and guar gum. 14.The pharmaceutical composition defined in claim 2 wherein the compressedannular tablet is chewable and comprises one or more pharmaceuticallyacceptable, excipients suitable for a chewable medication and aflavoring agent.
 15. A pharmaceutical composition which comprises: (a)an intraorally releasing first portion, in the form of a moldedtriturate tablet comprising a therapeutically effective amount of apharmaceutically active ingredient selected from the group consisting ofbuprenorphine, phentanyl, or ergotamine in a dosage of no more thanabout 50 mg, wherein the molded triturate tablet disintegrates ordissolves within 10 minutes permitting rapid release of thepharmaceutically active ingredient, when the composition is contactedwith saliva during intraoral administration and (b) a second releasingportion located around the first portion as a compressed annular tablet,comprising a therapeutic ingredient capable of oral administration andwhich is releasable and orally ingestible by the patient after themolded triturate has disintegrated or has dissolved intraorally.
 16. Thepharmaceutical composition defined in claim 1 wherein the compressedannular tablet containing the pharmaceutically active ingredient capableof oral administration remains substantially intact until the intraoraladministration of the pharmaceutically active ingredient capable ofintraoral administration has been completed.
 17. The pharmaceuticalcomposition defined in claim 1 wherein the pharmaceutically activeingredient capable of intraoral administration has a rapid onset of thedesired therapeutic effect through intraoral absorption.
 18. Thepharmaceutical composition defined in claim 1 wherein thepharmaceutically active ingredient capable of intraoral administrationis selected from the group consisting of analgesics, antihistamines,antidiarrheal, anxiolytic, hypnotics, stimulants, cardiovascular drugs,pulmonary drugs, antihypertensives, antiemetics, anti-inflammatorydrugs, renal drugs, steroids, anti-psychotic drugs, and antidiabeticdrugs.
 19. A process for the preparation of a pharmaceutical compositionin unit dosage form as a compressed annular tablet with molded trituratetablet for both intraoral and oral administration to a patient, saidpharmaceutical composition to be placed intraorally of said patient,which comprises: (a) as a first releasing portion, a molded trituratetablet comprising a therapeutically effective amount of at least onepharmaceutically active ingredient capable of intraoral administrationhaving a molecular weight of less than 350, in a dosage of no more thanabout 50 mg, wherein the molded triturate tablet comprises an excipientand disintegrates or dissolves within 10 minutes permitting rapidrelease of the pharmaceutically active ingredient; and (b) as a secondreleasing portion located around said first portion, a therapeuticallyeffective amount of at least one pharmaceutically active ingredientcapable of oral administration and which is releasable and orallyingestible by the patient after the inlaid triturate has disintegratedor has dissolved intraorally, which comprises the step of: (i) providingthe second portion as a single- or multi-layer compressed annulartablet, and (ii) molding the first portion as a triturate tablet intothe annulus of (i).
 20. A method of administering a pharmaceuticalcomposition in unit dosage form as a compressed annular tablet moldedtriturate tablet for both intraoral and oral administration to apatient, which comprises: (a) as a first releasing potion, a moldedtriturate tablet comprising a therapeutically effective amount of atleast one pharmaceutically active ingredient capable of intraoraladministration having a molecular weight of less than 350, in a dosageof no more than about 50 mg, wherein the molded triturate tabletcomprises an excipient and disintegrates or dissolves within 10 minutespermitting rapid release of the pharmaceutically active ingredient has;and (b) as a second releasing portion located around the said firstportion, a therapeutically effective amount of at least onepharmaceutically active ingredient capable of oral administration andwhich is releasable and orally ingestible by the patient after theinlaid triturate has disintegrated or has dissolved intraorally, whichcomprises the steps of: (i) placing the pharmaceutical composition underthe tongue or against the inner wall of the cheek or within thevestibular mucosa of said patient; (ii) retaining the pharmaceuticalcomposition under the tongue or against the inner wall of the cheek orvestibular mucosa of the patient until the fit releasing portion of thepharmaceutical composition containing the pharmaceutically activeingredient capable of intraoral administration has dissolved or hasdisintegrated hereby substantially releasing the pharmaceutically activeingredient capable of intraoral administration; and (iii) following step(ii) sucking or swallowing whole or chewing and swallowing the secondreleasing portion of the pharmaceutical composition.
 21. Thepharmaceutical composition defined in claim 1 wherein thepharmaceutically active indent capable of intraoral administration has afirst pass metabolism which is avoided by intraoral administration. 22.The pharmaceutical composition defined in claim 1 wherein thepharmaceutically active ingredient capable of intraoral administrationhas a rapid onset of desired therapeutic effect through intraoralabsorption.